Aminomethyl oxooxazolidinyl cycloalkylbenzene derivatives useful as antibacterial agents

ABSTRACT

Aminomethyl oxooxazolidinyl cycloalkylbenzene derivatives, such as l-N-[3-(2,3-dihydro-1-oxo-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]acetamide, possess useful antibacterial activity.

This is a division of application Ser. No. 07/233,828, filed Aug. 19,1988 now U.S. Pat. No. 4,921,869 which is a divisional of Ser. No.07/106,358 filed Oct. 9, 1987 now U.S. Pat. No. 4,801,600.

TECHNICAL FIELD

This invention relates to novel aminomethyl oxooxazolidinylcycloalkylbenzene derivatives, their preparation, to pharmaceuticalcompositions containing them, and to methods of using them to alleviatebacterial infections.

BACKGROUND OF THE INVENTION

At the present time, no existing antibacterial product provides allfeatures deemed advantageous. There is continual development ofresistance by bacterial strains. A reduction of allergic reactions andof irritation at the site of injection, and greater biological half-life(i.e., longer in vivo activity) are currently desirable features forantibacterial products.

U.S. Pat. No. 4,128,654 issued to Fugitt et al. on Dec. 5, 1978,discloses, among others, compounds of the formula: ##STR1## where

A=RS(O)_(n) ;

X=Cl, Br or F;

R=C₁ -C₃ alkyl; and

n=0, 1 or 2.

The compounds are disclosed as being useful in controlling fungal andbacterial diseases of plants.

U.S. Reissue Pat. No. 29,607 reissued Apr. 11, 1978 disclosesderivatives of 5-hydroxymethyl-3-substituted-2-oxazolidinones of theformula: ##STR2## where R is H, F, CH₃, or CF₃. Such compounds aredescribed as having antidepressive, tranquilizing, sedative, andantiinflammatory properties.

U.S. Pat. No. 4,250,318, which was issued on Feb. 10, 1981, disclosesantidepressant compounds of the formula: ##STR3## where R' can be, amongothers, a para-n-pentylamino group, an SR₁ group where R₁ is C₁ -C₅alkyl, or an acetylmethylthio group.

U.S. Pat. No. 4,340,606 issued to Fugitt et al. on July 20, 1982,discloses antibacterial agents of the general formula: ##STR4## where

R₁ ═CH₃, C₂ H₅, CF₂ H, CF₃ or CF₂ CF₂ H; and

X═OR₂ (R₂ ═H or various acyl moieties).

U.S. Pat. No. 3,687,965, issued to Fauran et al. on Aug. 29, 1972,discloses compounds of the formula: ##STR5## where

--N(R₁)(R₂) represents either dialkylamino radical in which the alkylportions have one to five carbon atoms, or a heterocyclic amino radicalwhich may be substituted by an alkyl radical having one to five carbonatoms or by a pyrrolidinocarbonylmethyl radical, and

R₃ represents a phenyl radical which may be substituted by one or moreof the following radicals:

an alkoxy radical having one to five carbon atoms;

a halogen atom;

a trifluoromethyl radical, or

a carboxyl radical which may be esterified.

The patent states that these compounds possess hypotensive,vasodilatatory, spasmolytic, sedative, myorelaxant, analgesic andantiinflammatory properties. There is no mention of antibacterialproperties.

Belgian Patent No. 892,270, published Aug. 25, 1982, discloses monoamineoxidase inhibitors of the formula ##STR6## where

R is H, C₁ -C₄ alkyl or propargyl;

Ar is phenyl, optionally substituted by halo or trifluoromethyl;

n is 0 or 1; and

X is --CH₂ CH₂ --, --CH═CH--, an acetylene group or --CH₂ O--.

U.S. Pat. No. 4,461,773 issued to W. A. Gregory on July 24, 1984,discloses antibacterial agents of the formula ##STR7## wherein, for thel, and mixtures of the d and l stereoisomers of the compound,

R₁ is R₂ SO₂, ##STR8##

R₃ and R₄ are independently H, alkyl of 1-4 carbons or cycloalkyl of 3-8carbons;

R₅ is NR₃ R₄ or OR₃ ;

R₆ is alkyl of 1-4 carbons;

R₇ is alkyl of 1-4 carbons, optionally substituted with one or morehalogens;

R₈ and R₉ are independently alkyl of 1-4 carbons or, taken together are--(CH₂)_(p) --;

R₁₀ is H, alkyl of 1-3 carbons, --CR₁₁, ##STR9##

R₁₁ is alkyl of 1-12 carbons;

R₁₂ is H, alkyl of 1-5 carbons, CH₂ OH or CH₂ SH;

X is Cl, Br or I;

Z is a physiologically acceptable cation;

m is 2 or 3;

n is 0 or 1; and

p is 3, 4 or 5;

and when R₁₀ is alkyl of 1-3 carbons, R₁ can also be CH₃ S(O)_(q) whereq is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

European Patent Application Nos. 127,902, published Dec. 12, 1984, and184,170, published June 11, 1986, disclose antibacterial agents of theformula: ##STR10## wherein, for the l, and mixtures of the d and lstereoisomers of the compound,

A is --NO₂, --S(O)_(n) R₁, --S(O)₂ --N═S(O)_(p) R₂ R₃, --SH, ##STR11##of 1 to 8 carbons, optionally substituted with one or more halogenatoms, OH, ═O other than at alpha position, S(O)_(n) R₂₄, NR₅ R₆,alkenyl of 2-5 carbons, alkynyl of 2-5 carbons or cycloalkyl of 3-8carbons;

R₁ is C₁ -C₄ alkyl, optionally substituted with one or more halogenatoms, OH, CN, NR₅ R₆ or CO₂ R₈ ; C₂ -C₄ alkenyl; ##STR12##

R₂ and R₃ are independently C₁ -C₂ alkyl or, taken together are--(CH₂)_(q) --;

R₄ is alkyl of 1-4 carbons, optionally substituted with one or morehalogens;

R₅ and R₆ are independently H, alkyl of 1-4 carbons or cycloalkyl of 3-8carbons;

R₇ is --NR₅ R₆, --OR₅ or ##STR13##

R₈ is H or alkyl of 1-4 carbons;

R₉ is H, C₁ -C₄ alkyl or C₃ -C₈ cycloalkyl;

R₁₀ is H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₃ -C₄ cycloalkyl, --OR₈ or--NR₁₁ R_(11A) ;

R₁₁ and R_(11A) are independently H or C₁ -C₄ alkyl, or taken together,are --(CH₂)_(r) --;

X is Cl, Br or I;

Y is H, F, Cl, Br, alkyl or 1-3 carbons, or NO₂, or A and Y takentogether can be --O--(CH₂)_(t) O--;

Z is a physiologically acceptable cation;

n is 0, 1 or 2;

p is 0 or 1;

q is 3, 4 or 5;

r is 4 or 5;

t is 1, 2 or 3;

B is --NH₂, ##STR14## or N₃ ;

R₁₂ is H, C₁ -C₁₀ alkyl or C₃ -C₈ cycloalkyl;

R₁₃ is H; C₁ -C₄ alkyl optionally substituted with one or more halogenatoms; C₂ -C₄ alkenyl; C₃ -C₄ cycloalkyl; phenyl; ##STR15## theaminoalkyl groups derived from α-amino acids such as glycine, L-alanine,L-cysteine, L-proline, and D-alanine; --NR₁₉ R₂₀ ; or C(NH₂)R₂₁ R₂₂ ;

R₁₄ is C₁ -C₄ alkyl, optionally substituted with one or more halogenatoms;

R₁₅ is H or C₁ -C₄ alkyl, optionally substituted with one or morehalogen atoms;

R₁₆ and R₁₇ are independently C₁ -C₄ alkyl or, taken together, are--(CH₂)_(m) --;

R₁₈ is C₁ -C₄ alkyl or C₇ -C₁₁ aralkyl;

R₁₉ and R₂₀ are independently H or C₁ -C₂ alkyl;

R₂₁ and R₂₂ are independently H, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, phenylor, taken together, are --(CH₂)_(s) --;

u is 1 or 2;

v is 0, 1 or 2;

m is 2 or 3;

s is 2, 3, 4 or 5; and

R₂₃ is H, alkyl of 1-8 carbons optionally substituted with one or morehalogens, or cycloalkyl of 3-8 carbons;

R₂₄ is alkyl of 1-4 carbons or cycloalkyl of 3-8 carbons;

R₂₅ is alkyl of 1-4 carbons substituted with one or more of --S(O)_(n)R₂₄, ##STR16## or alkenyl of 2-5 carbons optionally substituted withCHO; or a pharmaceutically suitable salt thereof; provided that:

(1) when A is CH₃ S--, then B is not ##STR17##

(2) when A is CH₃ SO₂ --, then B is not ##STR18##

(3) when A is H₂ NSO₂ -- and B is ##STR19## then R₁₂ is H;

(4) when A is --CN, B is not --N₃ ;

(5) when A is (CH₃)₂ CH, B is not NHCOCH₂ Cl;

(6) when A is OR₅, then B is not NH₂ ;

(7) when A is F, then B is not NHCO₂ CH₃.

None of the above-mentioned references suggest the novel antibacterialcompounds of this invention.

SUMMARY OF THE INVENTION

According to the present invention, there is provided an oxazolidinonehaving the formula: ##STR20##

wherein for the l isomer or racemic mixtures containing it

B is NH₂, ##STR21##

u is 1 or 2;

R₃ is H, alkyl of 1-10 carbon atoms, or cycloalkyl of 3-8 carbon atoms;

R₄ is H, alkyl of 1-4 carbon atoms, alkenyl of 2-4 carbon atoms,cycloalkyl of 3-4 carbon atoms, or OR₅ ;

R₅ is alkyl of 1-4 carbon atoms;

X is CH₂, O, S, or NR₆ ;

R₆ is H or alkyl of 1-4 carbon atoms;

n is 1-3; and

R₁ and R₂ taken together are ##STR22## or a pharmaceutically suitablesalt thereof; provided that:

(1) when n is 2, then X is not S; and

(2) when n is 3, then X is not O or NR₆.

Also provided is a process for preparing compounds of Formula (I), sucha process being described in detail hereinafter.

Additionally provided are a pharmaceutical composition containing acompound of Formula (I) and a method of using a compound of Formula (I)to treat a bacterial infection in a mammal.

PREFERRED EMBODIMENTS

Preferred compounds are the oxazolidinones of Formula (I) wherein:

(a) B is ##STR23## where R₄ is H, CH₃, or OR₅ ; or

(b) R₁ and R₂ taken together are ##STR24## or

(c) n is 1-2; or

(d) X is CH₂.

More preferred compounds are the oxazolidinones of Formula (I) wherein:

(a) B is ##STR25## or

(b) R₁ and R₂ taken together are ##STR26## or

(c) n is 1; or

(d) X is CH₂.

Specifically preferred are the following compounds:

(l)-N-[3-(2,3-dihydro-1-oxo-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]acetamide;

(l)-N-[3-(2,3-dihydro-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]acetamide;

(l)-N-[3-(2,3-dihydro-1-hydroxy-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]acetamide.

DETAILED DESCRIPTION

The compounds of Formula (I) contain at least one chiral center and, assuch, exist as two individual isomers or as a mixture of both. Thisinvention relates to the levorotatory isomer (l), which for many of thecompounds in this invention can be referred to as the (S) isomer, aswell as mixtures containing both the (R) and (S) isomers. Additionalchiral centers may be present in the B group, or when R₁ and R₂ takentogether are H and OH or H and N(R₆)₂. The invention relates to allpossible stereoisomers of the above.

For the purposes of this invention, the l-isomer of compounds of Formula(I) is intended to mean compounds of the configuration depicted; when Bis NHAc, and closely related groups, this isomer is described as the(S)-isomer in the Cahn-Ingold-Prelog nomenclature: ##STR27##

Synthesis

Compounds of Formula (I) where R₁ and R₂ taken together are H₂, and Xand n are as previously defined, can be prepared as follows: ##STR28##

Compounds of Formula (II) are converted to isocyanates (III) bytreatment of their hydrochloride salts with phosgene in a refluxingsolvent such as xylene. Other solvents such as benzene or toluene may beused. Isocyanates (III) react with glycidyl butyrate in the presence oflithium bromide and tributylphosphine oxide in refluxing xylene ortoluene to afford oxazolidinones (IV). Compounds (IV), upon treatmentwith sodium methoxide in methanol or sodium ethoxide in ethanol at 0° C.to room temperature give alcohols (V). Then alcohols (V) can beconverted to compounds (VI)-(XI) by the process previously described inpublished European applications Nos. 127,902 and 184,170. L₁ is aleaving group which can be Cl, Br, I, OMs or OTs. L₂ is also a leavinggroup and can be Cl, Br, or I.

Glycidyl butyrate can be resolved by procedures described in W. E.Ladner and G. M. Whitesides, J. Am. Chem. Soc., 106, 7250 (1984). Byusing (R)-glycidyl butyrate in the synthesis, l-isomer of compounds ofFormula (I) can be prepared.

Compounds of Formula (I) where R₁ and R₂ taken together are not H₂ butas described previously can be prepared as follows: ##STR29##

Oxidation of compounds of Formula (XII) with chromium (VI) oxide inacetic acid and acetic anhydride at room temperature affords ketones(XIII). When X═S, the sulfur might be oxidized to sulfoxide or sulfoneby the above reaction condition. However, they can be easily reducedback to sulfide by catalytic hydrogenation in an alcoholic solvent suchas ethanol.

Ketones (XIII) can then be converted to compounds (XIV)-(XVII) bystandard procedures. For example, an alkali metal borohydride such assodium borohydride in a solvent such as methanol or ethanol at 0° C. toroom temperature reduces the ketone to hydroxy group to give compounds(XIV). Reaction of (XIII) with (R₆)₂ NH in the presence of sodiumcyanoborohydride in an alcoholic solvent such as methanol or ethanol atroom temperature to 80° C. yields amines (XV). Treatment of (XIII) withhydroxyamine hydrochloride or H₂ NOR₅ in the presence of a base such aspyridine or triethylamine in an alcoholic solvent such as methanol orethanol at room temperature to 100° C. gives oximes (XVI). Thepreparation of (XVII) is described below in Example 18 by reacting(XIII) with 1-amino-4-methyl piperazine in a refluxing solvent such astetrahydrofuran (THF) or dioxane containing boron trifluoride etherate.

Pharmaceutically suitable salts of compounds of Formula (I) can beprepared in a number of ways known in the art. When R₁, R₂, X or Bcontain a basic nitrogen, pharmaceutically salts include those resultingfrom treatment with acids such as acetic, hydrochloric, sulfuric,phosphoric, succinic, fumaric, ascorbic, and glutaric acid.

The invention can be further understood by the following examples inwhich parts and percentages are by weight unless indicated otherwise.

EXAMPLE 1 Preparation of(l)-N-[3-(2,3-Dihydro-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]acetamide(I; R₁ ═R₂ ═H, X═CH₂, n=1, B═NHCOCH₃) Part A: Preparation of5-Isocyanateindan (III, X═CH₂, n=1)

HCl gas was bubbled through a solution of 5-aminoindan (20 g, 0.15 mol)in xylene (400 mL) for 30 minutes. The mixture was then brought toreflux and phosgene was bubbled through while refluxing. When reactionwas complete, nitrogen was bubbled through while the reaction cooled.Xylene was removed in vacuo and the resulting isocyanate (III, X═CH₂,n=1) was directly submitted to the next reaction.

Part B: Preparation of(l)-N-[3-(2,3-Dihydro-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]butyrate(IV, X═CH₂, n=1)

A solution of lithium bromide (0.78 g, 9 mmol) and tributylphosphineoxide (1.96 g, 9 mmol) in xylene (200 mL) was refluxed for one hour. Theheat was removed and a solution of isocyanate (III, X═CH₂, n=1) fromPart A and (R)-glycidyl butyrate (18.6 g, 0.13 mol) in xylene (75 mL)was added slowly. After refluxing for one hour, xylene was removed invacuo, the residue was diluted with methylene chloride and washed withbrine. The separated organic layer was dried (MgSO₄). Purification ofthe crude product by flash column chromatography gave 26 g (67%) of thetitle compound (IV, X═CH₂, n=1). IR (neat): 1752 cm⁻¹ ; NMR (CDCl₃) δ:7.43 (S,1H), 7.18 (S,2H), 4.83 (m,1H), 4.33 (2dd,2H), 4.10 (t,1H), 3.80(dd,1H), 2.88 (dd,4H), 2.33 (t, 2H), 2.07 (p,2H), 1.60 (m,2H), 0.92(t,3H); MS: m/z 303.1470 (M⁺) calcd for C₁₇ H₂₁ NO₄, 303.1471; [α]_(D)=-42° (C=0.8, CHCl₃)

Part C: Preparation of(l)-5-Hydroxymethyl-N-[3-(2,3-dihydro-1H-inden-5-yl)-2-oxooxazolidin](V, X═CH₂, n=1)

Butyrate (IV, X═CH₂, n=1) (39 g, 0.13 mol) was treated with sodiummethoxide (710 mg, 13 mmol) in methanol (500 mL) at room temperature forone hour. After removing methanol, the residue was taken up with 10%methanol-methylene chloride and the solid was filtered off. Removal ofthe solvent afforded 24.7 g (82%) of the title compound (V, X═CH₂, n=1)as a white solid, m.p. 209°-212° C.; NMR (CDCl₃) δ: 7.43 (s,1H), 7.20(s,2H), 4.72 (m,1H), 3.99 (m,3H), 3.76 (m,1H), 2.87 (dd,4H), 2.68(bs,1H,OH), 2.07 (p,2H).

Part D: Preparation of(l)-5-Azidomethyl-N-[3-(2,3-dihydro-1H-inden-5-yl)-2-oxooxazolidin] (VI,X═CH₂, n=1)

To a solution of alcohol (V, X═CH₂, n=1) (23 g. 0.099 mol) in methylenechloride (300 mL) and triethylamine (28 mL) at 0° C. was added mesyl(Ms) chloride (22.5 g, 0.19 mol). The mixture was then stirred at roomtemperature for one hour. Additional mesyl chloride (6 g, 0.05 mol) andtriethylamine (7.3 mL) were added and the reaction was continuallystirred for two hours. It was washed with brine, the separated organiclayer was dried (MgSO₄) and the solvent was evaporated to give 30.8 g ofthe mesylate which was dissolved in DMF (500 mL) and treated with sodiumazide (12.9 g, 0.198 mol) at 85° C. for six hours. The reaction mixturewas diluted with water and extracted with methylene chloride five times.The combined organic layer was washed with brine and dried (MgSO₄).Removal of the solvent in vacuo yielded 26 g (100%) of the titlecompound (VI, X═CH₂, n=1) as a solid. IR (nujol): 2101,1730 cm⁻¹ ; NMR(CDCl₃) δ: 7.42 (s,1H), 7.17 (s,2H), 4.73 (m,1H), 4.05 (t,1H), 3.80(dd,1H), 3.63 (2dd,2H), 2.85 (dd,4H), 2.05 (p,2H); [α]_(D) =-122° (C=1,CH₃ CN).

Part E: Preparation of(l)-5-Aminomethyl-N-[3-(2,3-dihydro-1H-inden-5-yl)-2-oxooxazolidin]hydrochloride(VII, X═CH₂, n=1)

To a solution of azide (VI, X═CH₂, n=1) (25 g, 0.097 mol) in glyme (400mL) was added trimethylphosphite (14.9 mL, 0.13 mol) and the mixture washeated at 65° C. for one hour. Then 10 mL of 50% hydrochloric acid wasadded and the reaction was refluxed for eleven hours. Additional 15 mLof 50% hydrochloric acid was added and it was continually refluxed for1.5 hours. Removal of the solvent in vacuo and the residue was washedwith glyme followed by drying under high vacuum to afford 8.7 g (34%) ofthe title compound (VII, X═CH₂, n=1). m.p. >219° C. (dec).

Part F: Preparation of(l)-N-[3-(2,3-Dihydro-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]acetamide(I; R₁ ═R₂ ═H, X═CH₂, n=1, B═NHCOCH₃)

A solution of the hydrochloride salt (VII, X═CH₂, n=1) (8.7 g, 32 mmol)in THF-H₂ O (30 mL - 5 mL) was neutralized with 2N sodium hydroxideaqueous solution. Then acetic anhydride (4.14 g, 41 mmol) was added.More sodium hydroxide solution was added to adjust pH to 6-7.Tetrahydrofuran was removed and the aqueous layer was extracted withchloroform three times. The chloroform layer was washed with brine anddried (MgSO₄). Removal of the solvent gave 8.8 g (100%) of(l)-N-[3-(2,3-dihydro-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]acetamideas a white solid. m.p. 131°-133° C.; IR (nujol): 1735, 1655 cm⁻¹ ; NMR(CDCl₃) δ: 7.37 (s,1H), 7.17 (s,2H), 6.47 (bs,1H), 4.73 (m,1H), 4.02(t,1H), 3.78 (dd,1H), 3.63 (m,2H), 2.87 (dd,4H), 2.07 (p,2H), 2.00(s,3H); MS: m/z 274.1310 (M⁺), calcd. for C₁₅ H₁₈ N₂ O₃, 274.1317;[α]_(D) =-31° (C=1, CH₃ CN).

By using the procedures described in Example 1, the following compoundsin Table I were prepared or can be prepared.

                                      TABLE I                                     __________________________________________________________________________     ##STR30##                                                                    Ex.                                                                              X   n B       Isomer                                                                            m.p. (°C.)                                                                   [α]D                                         __________________________________________________________________________    1D CH.sub.2                                                                          1 N.sub.3 l         -122° (c = 1, CH.sub.3 CN)                  1E CH.sub.2                                                                          1 NH.sub.2                                                                              l   >219 (dec, HCl salt)                                     1F CH.sub.2                                                                          1 NHCOCH.sub.3                                                                          l   131-133                                                                             -31° (c = 1, CH.sub.3 CN)                   2  CH.sub.2                                                                          1 NHCOCH.sub.3                                                                          dl                                                           3  CH.sub.2                                                                          1 NHCOC.sub.2 H.sub.5                                                                   l                                                            4  CH.sub.2                                                                          2 NHCOCH.sub.3                                                                          l                                                            5  CH.sub.2                                                                          3 NHCOCH.sub.3                                                                          l                                                            6  O   1 NHCO    dl                                                           7  O   1 NHCO.sub.2 CH.sub.3                                                                   l                                                            8  O   2 NHSOCH.sub.3                                                                          l                                                            9  O   2 N(CH.sub.3)COCH.sub.3                                                                 l                                                            10 S   1 NHCOCH.sub.3                                                                          l                                                            11 S   1 NHSO.sub.2 CH.sub.3                                                                   l                                                            12 S   3 NHCOC.sub.4 H.sub.9                                                                   l                                                            13 NH  1 NHCOCH.sub.3                                                                          l                                                            14 NCH.sub.3                                                                         2 N.sub.3 dl                                                           15 NC.sub.4 H.sub.9                                                                  2 NHSOC.sub.3 H.sub.7                                                                   l                                                            __________________________________________________________________________

EXAMPLE 16 Preparation of(l)-N-[3-(2,3-Dihydro-1-oxo-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]acetamide(I; R₁, R₂ ═O, X═CH₂, n=1, B═NHCOCH₃)

To a solution of chromium (VI) oxide (3.58 g, 35.8 mmol) in acetic acid(35 mL) and water (8.75 mL) was added compound (I) (R₁ ═R₂ ═H, X═CH₂,n=1, B═NHCOCH₃) (7 g, 25.5 mmol) in acetic acid (35 mL) and aceticanhydride (10.6 mL). The mixture was stirred at room temperatureovernight and then extracted with methylene chloride three times afteradding water. The combined organic layer was washed with saturatedsodium bicarbonate, brine, and dried (MgSO₄). Removal of the solventafforded the crude product which was purified by flash columnchromatography to yield 2.55 g (35%) of(l)-N-[3-(2,3-dihydro-1-oxo-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]acetamideas a white solid. m.p. 163°-165° C.; IR (CHCl₃): 1759, 1699, 1608 cm⁻¹ ;NMR(CDCl₃) δ: 7.73 (d,1H), 7.67 (s,1H), 7.50 (d,1H), 6.43 (bs,1H), 4.83(m,1H), 4.13 (t,1H), 3.88 (dd,1H), 3.70 (t,2H), 3.13 (t,2H), 2.70(t,2H), 2.03 (s,3H); MS: m/z 288.1116 (M⁺), calcd. for C₁₅ H₁₆ N₂ O₄,288.1110; [α]_(D) =-44° (C=1, CH₃ CN).

EXAMPLE 17 Preparation of(l)-N-[3-(2,3-Dihydro-1-hydroxy-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]acetamide(I; R₁, R₂ ═H, OH, X═CH₂, n=1, B═NHCOCH₃)

To a solution of(l)-N-[3-(2,3-dihydro-1-oxo-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]acetamide(0.5 g, 1.73 mmol) in ethanol (10 mL) and THF (2 mL) was added sodiumborohydride (265 mg, 6.94 mmol). The mixture was stirred at roomtemperature for three hours before quenching with 10% hydrochloric acid.Ethanol was removed, the residue was diluted with 10% hydrochloric acidand extracted with hot chloroform three times. The combined chloroformlayer was washed with brine and dried (Na₂ SO₄). Removal of the solventgave the crude product which was purified by flash column chromatographyto afford 385 mg (77%) of(l)-N-[3-(2,3-dihydro-1-hydroxy-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]acetamideas a white solid. m.p. 158°-159° C.; IR (nujol): 3286, 1737, 1653 cm⁻¹ ;NMR (d₆ -DMSO) δ: 8.27 (bs,1H), 7.40 (s,1H), 7.33 (s,2H), 5.22 (bs,1H),5.02 (bs,1H), 4.70 (m,1H), 4.10 (t,1H), 3.73 (t,1H), 3.40 (m,2H), 2.90(m,1H), 2.72 (m,1H), 2.33 (m,1H), 1.83 (s,3H), 1.77 (m,1H); MS: m/z290.1270 (M⁺), calcd. for C₁₅ H₁₈ N₂ O₄, 290.1267; [α]_(D) =-19° (C═1,CH₃ OH).

EXAMPLE 18 Preparation of(l)-N-[3-[1,2-Dihydro-1-(4-methyl-1-piperazinylimino)-1H-inden-5-yl]-2-oxooxazolidin-5-ylmethyl]acetamide(I, R₁, ##STR31##

A mixture of(l)-N-[3-(2,3-dihydro-1-oxo-1H-inden-5-yl)-2-oxooxazolidin-5-ylmethyl]acetamide(0.2 g, 0.69 mmol) and 1-amino-4-methylpiperazine (120 mg, 1.04 mmol) indioxane (5 mL) containing boron trifluoride etherate (0.05 mL) and 4 Amolecular sieves was refluxed overnight. The solvent was removed and theresidue was chromatographed to give 127 mg (48%) of the title compound.m.p. >200° C. (dec); NMR (d₆ -DMSO) δ: 8.27 (bs,1H), 7.67-7.50 (m,3H),4.73 (bs,1H), 4.13 (t,1H), 3.77 (t,1H), 3.40 (m,2H), 3.00 (m,2H), 2.80(m,6H), 2.46 (bs,4H), 2.18 (s,3H), 1.83 (s,3H); MS: m/z 385.2107 (M⁺),calcd. for C₂₀ H₂₇ N₅ O₃, 385.2114.

By using the procedures described in Examples 16-18, the followingcompounds in Table II were prepared or can be prepared.

                                      TABLE II                                    __________________________________________________________________________     ##STR32##                                                                    Ex.                                                                              X   n R.sub.1,R.sub.2                                                                            B       Isomer                                                                            m.p. (°C.)                                                                    [α]D                           __________________________________________________________________________    16 CH.sub.2                                                                          1 O            NHCOCH.sub.3                                                                          l   163-165                                                                              -44° (C = 1, CH.sub.3                                                  CN)                                  17 CH.sub.2                                                                          1 H,OH         NHCOCH.sub.3                                                                          l   158-159                                                                              -19° (C = 1, CH.sub.3                                                  OH)                                  18 CH.sub.2                                                                          1                                                                                ##STR33##   NHCOCH.sub.3                                                                          l   >200° (dec)                          19 CH.sub.2                                                                          1 H,NH.sub.2   NHCOCH.sub.3                                                                          l                                               20 CH.sub.2                                                                          1 H,N(CH.sub.3).sub.2                                                                        NHSOCH.sub.3                                                                          l                                               21 CH.sub.2                                                                          1 NOH          NHCOCH.sub.3                                                                          l                                               22 CH.sub.2                                                                          2  NOCH.sub.3  NH.sub.2                                                                              l                                               23 CH.sub.2                                                                          3                                                                                ##STR34##   N.sub.3 l                                               24 O   1 O            NHCOCH.sub.3                                                                          dl                                              25 O   1 H,OH         NHCO.sub.2 CH.sub.3                                                                   l                                               26 O   2 O            NHCOCH.sub.3                                                                          l                                               27 O   2                                                                                ##STR35##   NHSOC.sub.2 H.sub.5                                                                   l                                               28 S   1 H,OH                                                                                        ##STR36##                                                                            l                                               29 S   3 H,NH.sub.2   N(CH.sub.3)COCH.sub.3                                                                 l                                               30 NH  1 O            NHCOCH.sub.3                                                                          l                                               31 NCH.sub.3                                                                         2 H,OH         NHSO.sub.2 CH.sub.3                                                                   dl                                              32 NC.sub.4 H.sub.9                                                                  2 NOC.sub.4 H.sub.9                                                                          N.sub.3 dl                                              __________________________________________________________________________

Dosage Forms

The antibacterial agents of this invention can be administered by anymeans that produces contact of the active agent with the agents' site ofaction in the body of a mammal. They can be administered by anyconventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, butare generally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice.

The dosage administered will, of course, vary depending upon knownfactors such as the pharmacodynamic characteristics of the particularagent, and its mode and route of administration; age, health, and weightof the recipient; nature and extent of symptoms; kind of concurrenttreatment; frequency of treatment; and the effect desired. Usually, adaily dosage of active ingredient can be about 5 to 20 milligrams perkilogram of body weight. Ordinarily, when the more potent compounds ofthis invention are used, 5 to 15, and preferably 5 to 7.5 milligrams perkilogram per day, given in divided oral doses 2 to 4 times a day or insustained release form, is effective to obtain desired results. Thesedrugs may also be administered parenterally.

Projected therapeutic levels in humans should be attained by the oraladministration of 5-20 mg/kg of body weight given in divided doses twoto four times daily. The dosages may be increased in severe orlife-threatening infections.

Dosage forms (compositions) suitable for internal administration containfrom about 1.0 milligram to about 500 milligrams of active ingredientper unit. In these pharmaceutical compositions, the active ingredientwill ordinarily be present in an amount of about 0.5-95% by weight basedon the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, sucrose, manitol, starch, cellulose derivatives,magnesium stearate, stearic acid, and the like. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of hours. Compressed tablets can besugar coated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration contain preferably a watersoluble salt of the active ingredient, suitable stabilizing agents, and,if necessary, buffer substances. Antiooxidants such as sodium bisulfate,sodium sulfite, or ascorbic acid either alone or combined are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, A. Osol, a standard reference text in thisfield.

Useful pharmaceutical dosage forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 75 milligrams of powderedactive ingredient, 150 milligrams of lactose, 24 milligrams of talc, and6 mlligrams of magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in soybean oil is prepared and injectedby means of a positive displacement pump into gelatin to form softgelatin capsules containing 75 milligrams of the active ingredient. Thecapsules are washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 75 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 250 milligrams for microcrystalline cellulose, 11 milligramsof cornstarch and 98.8 milligrams of lactose. Appropriate coatings maybe applied to increase palatability or delay absorption.

Injectables

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is made isotonic withsodium chloride and sterilized.

Suspensions

An aqueous suspension is prepared for oral administration so that each 5milliliters contain 75 milligrams of finely-divided active ingredients.200 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodiumbenzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 millilitersof vanillin.

Utility

Test results indicate that the novel compounds of this invention arebiologically active against gram positive bacteria including multiplyantibiotic resistant strains of staphylococci and streptococci. Thesecompounds are potentially useful for the treatment of both human andanimal bacterial infections including diseases of the respiratory,gastrointestinal, genitourinary systems; blood; interstitial fluids; andsoft tissues.

As shown in Table III, compounds of Formula (I) exert an in vitroantibacterial effect. A standard microdilution method (NationalCommittee for Clinical Standards. Tentative standard M7-T. Standardmethods for dilution antimicrobial susceptibility tests for bacteriathat grow aerobically. National Committee for Clinical LaboratoryStandards, Villanova, Pa. 1982) with Mueller-Hinton broth is used todetermine the 24-hour minimal inhibitory concentrations (MIC's) for teststrains of Staphylococcus aureus and Escherichia coli.

The in vivo potency of these compounds is exemplified by the datasummarized in Table IV. Determinations of in vivo efficacy are performedby inoculating mice intraperitoneally with cultures of the infectingorganism diluted to produce 100% mortality in control animals withintwenty-four hours. The culture of S. aureus used to infect the animalswas diluted to the required bacterial density using 5% aqueous hoggastric mucin. The compounds are dissolved or suspended in 0.25% aqueousMethocel® (Methocel®: Hydroxypropyl Methylcellulose, E15 Premium, DowChemical Company) for oral administration or sterile distilled watercontaining 5% dimethylsulfoxide (Fisher Scientific Company, Fairlawn,N.J.) for subcutaneous administration. The mice are dosed at one hourand at four hours post-infection. Mortality is recorded daily until testtermination seven days post infection. The number of survivors in eachtreatment group on the seventh day after infection is used in thecalculation of the ED₅₀, the dose of compound that protects 50% of themice (Litchfield, J. T. and Wildoxon. A simplified method for evaluatingdose-effect experiments. J. Pharmacol Exp. Ther., 96:99-113, 1949).

                  TABLE III                                                       ______________________________________                                        In Vitro Broth Microdilution Minimal Inhibitory                               Concentrations (MIC's)                                                                 Minimum Inhibitory                                                            Concentration (μg/mL)                                             Ex. No.    Staphylococcus aureus                                                                        Escherichia coli                                    ______________________________________                                        1F         2              >128                                                16         2-4            >128                                                17         8              >128                                                18          8-16          >128                                                ______________________________________                                    

                  TABLE IV                                                        ______________________________________                                        In Vivo Activity of Compounds Against                                         Staphylococcus aureus                                                         in an Acute Lethal Mouse Model                                                ED.sub.50 (mg/kg)                                                             Ex. No. Oral Administration                                                                         Subcutaneous Administration                             ______________________________________                                        1F      2.2           1.7                                                     16      1.6           1.2                                                     17      1.9           1.8                                                     18      13.9          20.3                                                    ______________________________________                                    

What is claimed is:
 1. A compound having the formula ##STR37## whereinfor the l isomer or racemic mixtures containing it B is NH₂, ##STR38## uis 1 or 2; R₃ is H, alkyl of 1-10 carbon atoms, or cycloalkyl of 3-8carbon atoms;R₄ is H, alkyl of 1-4 carbon atoms, alkenyl of 2-4 carbonatoms, cycloalkyl of 3-4 carbon atoms, or OR₅ ; R₅ is alkyl of 1-4carbon atoms; X is O or S; R₆ is H or alkyl of 1-4 carbon atoms; n is1-3; and R₁ and R₂ taken together are ##STR39## or a pharmaceuticallysuitable salt thereof; provided that: (1) when n is 2, then X is not S;and(2) when n is 3, then X is not O.
 2. A compound of claim 1 wherein Bis ##STR40## where R₄ is H, CH₃, or OR₅.
 3. A compound of claim 1wherein n is 1 or
 2. 4. A compound of claim 1 wherein:(a) B is ##STR41##where R₄ is H, CH₃, or OR₅ ; and (b) n is 1 or
 2. 5. A compound of claim1 wherein B is ##STR42##
 6. A compound of claim 5 wherein n is
 1. 7. Apharmaceutical composition consisting essentially of a pharmaceuticallysuitable carrier and an antibacterial amount of a compound of claim 1.8. A pharmaceutical composition consisting essentially of apharmaceutically suitable carrier and an antibacterial amount of acompound of claim
 2. 9. A pharmaceutical composition consistingessentially of a pharmaceutically suitable carrier and an antibacterialamount of a compound of claim
 3. 10. A pharmaceutical compositionconsisting essentially of a pharmaceutically suitable carrier and anantibacterial amount of a compound of claim
 4. 11. A pharmaceuticalcomposition consisting essentially of a pharmaceutically suitablecarrier and an antibacterial amount of a compound of claim
 5. 12. Apharmaceutical composition consisting essentially of a pharmaceuticallysuitable carrier and an antibacterial amount of a compound of claim 6.13. A method of treating a bacterial infection in a mammal comprisingadministering to the mammal an antibacterial amount of a compound ofclaim
 1. 14. A method of treating a bacterial infection in a mammalcomprising administering to the mammal an antibacterial amount of acompound of claim
 2. 15. A method of treating a bacterial infection in amammal comprising administering to the mammal an antibacterial amount ofa compound of claim
 3. 16. A method of treating a bacterial infection ina mammal comprising administering to the mammal an antibacterial amountof a compound of claim
 4. 17. A method of treating a bacterial infectionin a mammal comprising administering to the mammal an antibacterialamount of a compound of claim
 5. 18. A method of treating a bacterialinfection in a mammal comprising administering to the mammal anantibacterial amount of a compound of claim 6.